Detection of hypermethylation of the p16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus

被引:117
作者
Kaneto, H
Sasaki, S
Yamamoto, H
Itoh, F
Toyota, M
Suzuki, H
Ozeki, I
Iwata, N
Ohmura, T
Satoh, T
Karino, Y
Satoh, T
Toyota, J
Satoh, M
Endo, T
Omata, M
Imai, K
机构
[1] Sapporo Med Univ, Dept Internal Med 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
[2] Sapporo Kohsei Gen Hosp, Dept Gastroenterol 3, Sapporo, Hokkaido, Japan
[3] Sapporo Kohsei Gen Hosp, Dept Clin Pathol, Sapporo, Hokkaido, Japan
[4] Sapporo Med Univ, Dept Clin Pathol, Sapporo, Hokkaido, Japan
[5] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo 1138655, Japan
关键词
hypermethylation; p16; hepatocarcinogenesis; preneoplastic diseases; hepatitis virus infection; methylation specific PCR;
D O I
10.1136/gut.48.3.372
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background/aim-Inactivation of the p16(INK4A) (p16) tumour suppressor gene by promoter region hypermethylation has been demonstrated not only in many types of tumours, including hepatocellular carcinoma (HCC), but also in early preneoplastic lesions in the lung, colon, oesophagus, and pancreas. The aim of this study was to examine the methylation status of the p16 promoter in pre- and/or non-neoplastic liver diseases. Patients/subjects/methods-The methylation status of p16 was evaluated in 22 HCC, 17 cirrhosis, 17 chronic hepatitis, nine primary biliary cirrhosis (PBC), eight autoimmune hepatitis, seven drug induced liver disease, six fatty liver, and three normal Liver tissues using methylation specific polymerase chain reaction (MSP). p16 protein expression was also examined by immunohistochemical staining. Results-Methylation of the p16 promoter was detected in HCC (72.7%, 16/22) and also in cirrhosis (29.4%, 5/17) and chronic hepatitis (23.5%, 4/17), all of which were positive for hepatitis B or C virus infections. Methylation was not detected in any of the other samples. All methylation positive HCC, cirrhosis, and chronic hepatitis samples showed loss of p16 expression, and a significant correlation was found between methylation and loss of expression. Analysis of serial samples from individual patients with methylation positive HCC revealed that loss of p16 expression with promoter methylation occurred in 18 of 20 patients at the stage of chronic hepatitis without clinically detectable carcinoma. Conclusions-Our results suggest that methylation of the p16 promoter and the resulting loss of p16 protein expression are early events in a subset of hepatocarcinogenesis and that their detection is useful in the follow up of patients with a high risk of developing HCC, such as those with hepatitis B or C viral infections.
引用
收藏
页码:372 / 377
页数:6
相关论文
共 50 条
[11]   Inactivation of p16INK4a by CpG hypermethylation is not a frequent event in colorectal cancer [J].
Norrie, MWA ;
Hawkins, NJ ;
Todd, AV ;
Meagher, AP ;
O'Connor, TW ;
Ward, RL .
JOURNAL OF SURGICAL ONCOLOGY, 2003, 84 (03) :143-150
[12]   Promoter hypermethylation of Wnt pathway inhibitors in hepatitis C virus - induced multistep hepatocarcinogenesis [J].
Umer, Muhammad ;
Qureshi, Sohail Asif ;
Hashmi, Zahid Yasin ;
Raza, Asif ;
Ahmad, Janbaz ;
Rahman, Moazur ;
Iqbal, Mazhar .
VIROLOGY JOURNAL, 2014, 11
[13]   p16INK4a promoter methylation and 9p21 allelic loss in colorectal carcinomas:: relation with immunohistochemical p16INK4a expression and with tumor budding [J].
Prall, F ;
Ostwald, C ;
Weirich, V ;
Nizze, H .
HUMAN PATHOLOGY, 2006, 37 (05) :578-585
[14]   Disease Progression from Chronic Hepatitis C to Cirrhosis and Hepatocellular Carcinoma is Associated with Increasing DNA Promoter Methylation [J].
Zekri, Abd El-Rahman Nabawy ;
Nassar, Auhood Abdel-Monem ;
El-Rouby, Mahmoud Nour El-Din ;
Shousha, Hend Ibrahim ;
Barakat, Ahmed Barakat ;
El-Desouky, Eman Desouky ;
Zayed, Naglaa Ali ;
Ahmed, Ola Sayed ;
Youssef, Amira Salah El-Din ;
Kaseb, Ahmed Omar ;
El-Aziz, Ashraf Omar Abd ;
Bahnassy, Abeer Ahmed .
ASIAN PACIFIC JOURNAL OF CANCER PREVENTION, 2013, 14 (11) :6721-6726
[15]   Hypermethylation of p16INK4a in Korean non-small cell lung cancer patients [J].
Hong, Young-Seoub ;
Roh, Mee-Sook ;
Kim, Na-Young ;
Lee, Hye-Jung ;
Kim, Hee-Kyoung ;
Lee, Kyung-Eun ;
Kwak, Jong-Young ;
Kim, Joon-Youn .
JOURNAL OF KOREAN MEDICAL SCIENCE, 2007, 22 :S32-S37
[16]   Epigenetic Silencing of p16INK4a gene in Sporadic Breast Cancer [J].
Satya P. Singh ;
Mallika Tewari ;
Alok K. Singh ;
Raghvendra R. Mishra ;
Hari S. Shukla .
Indian Journal of Surgical Oncology, 2023, 14 :822-828
[17]   Epigenetic Silencing of p16INK4a gene in Sporadic Breast Cancer [J].
Singh, Satya P. ;
Tewari, Mallika ;
Singh, Alok K. ;
Mishra, Raghvendra R. ;
Shukla, Hari S. .
INDIAN JOURNAL OF SURGICAL ONCOLOGY, 2023, 14 (04) :822-828
[18]   High frequency of p16INK4A gene alterations in hepatocellular carcinoma [J].
Liew, CT ;
Li, HM ;
Lo, KW ;
Leow, CK ;
Chan, JYH ;
Hin, LY ;
Lau, WY ;
Lai, PBS ;
Lim, BK ;
Huang, J ;
Leung, WT ;
Wu, S ;
Lee, JCK .
ONCOGENE, 1999, 18 (03) :789-795
[19]   High frequency of p16INK4A gene alterations in hepatocellular carcinoma [J].
Choong Tsek Liew ;
Hiu-Ming Li ;
Kwok-Wai Lo ;
Chon Kar Leow ;
John YH Chan ;
Lin Yee Hin ;
Wan Yee Lau ;
Paul Bo San Lai ;
Boon Kian Lim ;
Jin Huang ;
Wai Tong Leung ;
Shan Wu ;
Joseph Chuen Kwun Lee .
Oncogene, 1999, 18 :789-795
[20]   Status of p16INK4a and E-Cadherin Gene Promoter Methylation in Moroccan Patients With Cervical Carcinoma [J].
Attaleb, Mohammed ;
El hamadani, Wail ;
Khyatti, Meriem ;
Benbacer, Laila ;
Benchekroun, Nadia ;
Benider, Abdellatif ;
Amrani, Mariam ;
El Mzibri, Mohammed .
ONCOLOGY RESEARCH, 2009, 18 (04) :185-192